Autism spectrum disorders (ASDs) comprise a group of neurodevelopmental disorders that affect approximately 1 in 110 children (CDC, 2009). ASDs are characterized by the presence of three cardinal symptoms: social interaction deficits, repetitive or stereotyped behaviors, and abnormal language development. Though recent human genetics studies have identified several ASD candidate genes, the general mechanisms and brain circuitry involved in the etiology of these disorders remain largely undeciphered. The study of one gene in particular may be helpful in understanding the elusive disease mechanisms underlying ASDs. Shank3 is a scaffolding protein of the post-synaptic density that is the only member of the Shank family of proteins to be enriched in the striatum. Due to the multitude of studies connecting disruptions of Shank3 to affected human patients, this gene has become an attractive candidate gene for ASDs. Recently, our laboratory generated and characterized a novel Shank3B mutant mouse and discovered the presence of social interaction deficits and repetitive behaviors. Further investigation into the cause of these abnormalities identified defects in cortico-striatal synaptic transmission as well as several other striatal neuron aberrations. The long-term goal of this project is to understand the neural circuitry underlying the ASD-like behaviors in Shank3B mutant mice in order to identify potential targets for therapeutic intervention. I hypothesize that defective striatal circuitry plays a causative role in these abnormal behaviors. To directly test this hypothesis, I will generate a Shank3B conditional knockout mouse. I will then use this mouse to remove Shank3 exclusively from the striatum with the expectation that this region-specific ablation will recapitulate the repetitive behaviors and social interaction deficits found in the Shank3B mutant mice. To further probe the influence of defective striatal circuitry on these behaviors, I will then generate direct- and indirect pathway-specific Shank3 knockout mouse lines and analyze their social interactions and stereotyped behaviors. If successful, these studies could provide the first direct evidence for striatal dysfunction as a mechanism for repetitive behaviors and abnormal social interaction behaviors in an animal model of autism. PUBLIC HEALTH RELEVANCE: Recent studies have proposed disruption of the Shank3 gene to be the causative agent in several cases of human autism spectrum disorders (ASDs), specifically the 22q13.3 deletion syndrome. At the same time, behavioral analysis of the Shank3B mutant mouse revealed ASD-like behaviors, including social interaction deficits and compulsive grooming. This project will set out to understand the neuronal circuitry underlying the behavioral defects in the Shank3B mutant mouse, with the intended goal of identifying targets for future therapeutic interventions.